P010 - FERRITIN IRON IS CHEMICALLY REDUCED IN THE PRESENCE OF AGGREGATING Β-AMYLOID
Abstract
Aims
Low-oxidation-state (< 3+) iron phases associated with amyloid plaque pathology are implicated in Alzheimer’s disease pathogenesis, as they promote elevated redox activity and toxicity. The origin and mechanism for the formation of this iron remains unresolved, but may involve the interaction of the disease-related peptide β-amyloid with the iron storage protein ferritin. Here we have used synchrotron x-ray spectromicroscopy coupled with electron microscopy to establish the chemistry of β-amyloid/ferritin interactions.
Methods
β-amyloid (1-42) was incubated with ferritin in a buffer medium modelled on cerebral spinal fluid. The resulting β-amyloid/ferritin aggregates were examined using scanning transmission x-ray microscopy (STXM) at Diamond Light Source beamline I08 and the Swiss Light Source PolLux beamline. Measurements were performed at the carbon K-edge to detect organic constituents, and the calcium and iron L-edges to determine the distribution and chemical state of these metals. The spatial resolution for x-ray spectromicroscopy was 30-50 nm.
Results
STXM showed that the co-aggregation of β-amyloid and ferritin resulted in the conversion of ferritin’s inert ferric core into more reactive low-oxidation-states. The chemical composition of the in vitro aggregates formed in this study was shown to be analogous to primary components of amyloid plaque material extracted from the grey matter of Alzheimer's disease subjects.
Conclusions
These findings implicate β-amyloid in the altered iron metabolism and increased oxidative stress observed in Alzheimer’s disease. Amyloid-associated iron phases have biomarker potential to assist with disease diagnosis and staging, and may represent targets for therapies designed to lower oxidative stress in Alzheimer’s tissue.
